Nano material refers to the manipulation of matter on atom or molecular scale. One nanometer (nm) is one billionth, or 10−9, of a meter. By comparison, typical carbon-carbon bond lengths, or the spacing between these atoms in a molecule, are in the range 0.12-0.15 nm, and a DNA double-helix has a diameter around 2 nm. The definition used by the National Nanotechnology Initiative in the US, nano is a matter in the scale range of 1 to 100 nm [1]. Nano-particles are effectively a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nano-scale their properties becomes size-dependent. Nano-particles (nanoparticles and nano-particles are exchangeable in this invention) can strongly influence the mechanical properties of the material, like stiffness, elasticity, optical transparency, diffusive transport and shelf life stability [2]. Therefore they are very important for pharmaceutical, medical, food and personal care products.
In general terminology, researchers define nano-emulsions (nanoemulsions and nano-emulsions are exchangeable in this invention) as disruptions of nano-scale droplets formed by sheer-induced rupturing; micro-emulsions are usually formed by self-assembly. The micro-emulsions can also be formed with particle sizes smaller than 100 nm, spontaneous emulsification through the addition of a surfactant without a sheer usually related to the formation of equilibrium lyotropic of crystalline phases, in which the surface tension effectively vanishes and the droplets are formed by thermodynamic molecular self-assembly from the ‘bottom up’ [3].
As long as the particle size or matter is in nano scale, it can be called nano-emulsion (nanoemulsion) and nano-particle (nanoparticle). The micro-emulsion is in between nano-emulsion, mini-emulsion and emulsion. The micro-emulsion particle size can range from 20 nm to 200 nm or even larger.
Over the decades large molecules including biologically active compounds can only be effectively delivered across skin barriers via invasive methods such as needle injections. But this invasive method has obvious shortages due to safety issues and patient noncompliance issues such as pains. In addition to the safety concern and patient non-compliance issues from the invasive trans-dermal delivery methods, the demand for non-invasive trans-dermal delivery method has been increased more now than ever before due to more rapidly growing biotechnology derived molecules having much better therapeutic and/or cosmeceutical values than current therapies can provide. As can be expected, the non-invasive trans-dermal delivery technology of bio-active ingredients becomes very attractive and important in pharmaceutical industry as well as in cosmetics industry for better patient and consumer compliance. Unfortunately, to date there has been no suitable delivery method to meet this ever-increasing need for many obvious reasons. There have been at least two major obstacles: 1st one is that biologically active molecules are very sensitive to the environment during the manufacturing process, storage, transportation and application processes. Changes in temperature, pH, vibrations, light, ionic strength and other additives can easily denature or destroy its biological activity. Therefore the manufacturing process and other processes involving these molecules have to be very mild and gentle, the biological activity has to be maintained throughout the entire process; 2nd one is that the bio-molecules are large in size and difficult to get across the skin through its natural barriers. To overcome these and other practical obstacles, the delivery method has to possess the ability to enable large molecules to be delivered across each skin barrier (stratum corneum, epidermis and dermis), and the ability to maintain the biological activity throughout the whole delivering process.
With these two major requirements in place and other considerations for different bio-molecules, it's no wonder that there has been no suitable non-invasive trans-dermal method available to serve the purpose. Liposome technology has been used widely in the injectable pharmaceutical product to increase the drug active aqueous solubility and/or to have drug sustained-release characteristics such as Doxil [4, 5, 6, 7, and 8]. However, due to the higher than room temperature glass transition temperature (Tg) of phospho-choline lipids (PCs) and other lipids used in the liposome manufacturing technology, many bio-molecules cannot survive the higher temperature (i.e.: >50° C.) manufacturing process or the roughness of extrusion type processes [9]. Other micro-wounding methods such as micro-array (micro-needles) are used in cosmetics industry [10], but safety is still a major concern due to skin micro-wounds by itself and it cannot be easily operated.
Generally speaking human skin is about 250 um or less in thickness and its thickness varies in different skin sites for an individual. Human skin consists of top layer of stratum corneum, middle layer of epidermis, and lower layer of dermis where nerve terminals and cells are largely resided and abundant. Trans-dermal delivery pathways are considered to involve hair follicular channels, inter-cellular space, and intra-cellular space with the first two as the main routes [11]. As can be imagined, particle size and properties can also play important roles in the delivery of small and large molecules. Given its very small size and unique properties, nanoparticle can be a good candidate for such delicate process in trans-dermal delivery. The skin surface and the underneath are lipophilic and hydrophilic in nature, respectively. The inner skin layers and cells also have lipophilic in the cell membrane and hydrophilic inside the cells. To cross these multiple layers of skin and cells through lipophilic and hydrophilic membranes more than once, it would be very difficult for simple and single layer nanoparticle to accomplish this delicate task.
Therefore, multi-layer nanoparticles and nanoemulsions (smaller nanoparticles inside larger nanoparticles) encapsulated with active ingredients are selected, carefully designed and developed to serve this purpose. The main objective for these encapsulated multi-layer nanoparticles and nanoemulsions is to cross the skin layers without use of needles, and to deliver encapsulated contents into inner layers of skin during and after the penetration process by itself. Thus, many of experiments within this invention have been carried out to develop these multi-layer nanoparticles and nanoemulsions in very mild and gentle conditions with good stability, in an effort to encapsulate active ingredients, maintain their bio-activities and to overcome barriers from the multi-layer skin membranes of lipophilic and hydrophilic in nature.